International Medullary Thyroid Carcinoma Grading System: Detecting Adverse Outcomes

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In a study reported in the Journal of Clinical Oncology, Xu et al developed a two-tiered international medullary thyroid carcinoma grading system that identifies high-grade disease associated with poorer outcomes.

As stated by the investigators, “Currently, there is no widely accepted prognostically relevant pathologic grading system for medullary thyroid carcinoma… [T]here would be a clear advantage in developing a universal grading scheme with consensus cutoffs for all indices that has been validated in multiple international centers. We therefore created an international medullary thyroid carcinoma working group from five major centers with the goal of developing and validating an internationally accepted grading scheme for medullary thyroid carcinoma.”

Study Details

In the study, tumor tissue from 327 patients with medullary thyroid carcinoma from five centers in the United States, Europe, and Australia was analyzed for mitotic activity, Ki67 proliferative index, and necrosis using uniform criteria with blinding to other clinicopathologic features. A total of 10 grading systems, including the previously developed Sydney and Memorial Sloan Kettering Cancer grading systems, were evaluated using different cutoffs and combinations of the three variables. A single two-tiered grading system (the International Medullary Thyroid Carcinoma Grading System, or IMTCGS) was endorsed at a consensus conference attended by pathologists from all sites.

Key Findings

High-grade medullary thyroid carcinoma were defined as tumors with at least one of the following features: mitotic index ≥ 5 per 2 mm2, Ki67 proliferative index ≥ 5%, or tumor necrosis. On this classification, 81 (24.8%) of the medullary thyroid carcinomas were categorized as high-grade, with the remaining tumors categorized as low-grade.

On univariate analysis, the IMTCGS was a significant prognostic indicator for overall, disease-specific, distant metastasis–free, and locoregional recurrence–free survival (all P < .001). At 3, 5, and 10 years for low-grade vs high grade medullary thyroid carcinoma:

  • Overall survival was 96% vs 73%, 96% vs 66%, and 91% vs 47%
  • Disease-specific survival was 98% vs 78%, 98% vs 71%, and 97% vs 53%
  • Distant metastasis–free survival was 90% vs 44%, 88% vs 41%, and 84% vs 31%
  • Locoregional recurrence–free survival was 89% vs 47%, 85% vs 37%, and 82% vs 28%.

On multivariate analysis, patients with high-grade vs low-grade medullary thyroid carcinoma had significantly poorer overall (hazard ratio [HR] = 11.49, 95% confidence interval [CI] = 3.12–32.33, P < .001), disease-specific (HR = 8.49, 95% CI = 1.46­–49.33, P = .017), distant metastasis–free (HR = 2.49, 95% CI = 1.18–5.26, P = .017), and locoregional recurrence–free survival (HR = 2.11, 95% CI = 1.07–4.19, P = .032).

The significant prognostic ability of the IMTCGS was validated in analyses of cohorts from each of the five centers.

The investigators concluded, “This simple two-tiered international grading system is a powerful predictor of adverse outcomes in medullary thyroid carcinoma. As it is based solely on morphologic assessment in conjunction with Ki67 immunohistochemistry, it brings the grading of medullary thyroid carcinomas in line with other neuroendocrine tumors and can be readily applied in routine practice. We therefore recommend grading of medullary thyroid carcinomas on the basis of mitotic count, Ki67 proliferative index, and tumor necrosis.”

Ronald A. Ghossein, MD, of the Department of Pathology, Memorial Sloan Kettering Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by the National Cancer Institute and Italian Government-Ministry of Health. For full disclosures of the study authors, visit

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